Mitoxantrone is an anthracenedione derivative used in chemotherapy. It has demonstrated anti-tumor activity in a wide variety of experimental and human tumor models (Shenkenberg, T. D., et al., Annals of Internal Medicine, 105:67-81 (1986)). Phase III studies indicate activity in non-Hodgkin's lymphoma, myeloma, advanced breast cancer, bladder, ovarian and hepatocellular carcinomas in combination with other agents or as a single agent (Shenkenberg, T. D. et al., Annals of Internal Medicine, 105:67-81 (1986)). The toxic side effect of mitoxantrone is myelosuppression versus another related anthracycline such as doxorubicin which has a dose limiting cardiotoxicity (Saleton, S., Cancer Treatment Reviews, 14:297-303 (1987)). In addition to this, mitoxantrone proved to have a lower short and long term toxicity than doxorubicin. (Ehninger, G., et al., Clin. Phamacokinet, 18:365-380 (1990)). The precise mechanism of action for mitoxantrone is still under investigation, but it has been shown to be a DNA interchelator. As a result, it is thought that the main antitumor activity is conferred by inducing DNA strand breaks and by forming a complex with topoisomerase II (Ehninger, G., et al., Clin. Pharmacokinet, 18:365-380 (1990)).
It is well established in preclinical animal models that the therapeutic activity of anticancer agents can be improved through the use of liposome formulations. In general terms, liposomes engender pharmacokinetic and pharmacodistribution characteristics that give rise to increased therapeutic activity or reduced drug-related toxicity. Although the mechanism of therapeutic activity for liposomal anticancer agents is not well understood, studies have suggested that increased drug exposure at the site of tumor growth in an important attribute. Increases of tumor drug levels are a consequence of preferential accumulation of the liposome carrier within tumors. It is important to note that there is no evidence suggesting that the encapsulated form of the drug is therapeutically active, though it is postulated that antitumor activity is mediated by drug release from regionally localized liposomes.
The emphasis of investigators developing liposomal anticancer agents has, for the reasons cited above, been on using liposomal lipid compositions that: i) are less permeable to the encapsulated agent and ii) exhibit increased circulation lifetimes. Liposomes that are retained in the plasma compartment for extended periods exhibit a greater tendency to accumulate in regions of tumor growth. However, the kinetics of this extravasation process, where liposomes leave the blood compartment and enter an extravascular site, is slow. For this reason, efficient drug delivery can only be achieved with liposomes that effectively retain the drug.
Studies with liposomal formulation of the anthracycline doxorubicin suggest that properties which promote efficient delivery of drug to tumors also compromise therapeutic activity. A balance between doxorubicin retention (to maximize drug accumulation in a site of tumor growth) and release (to effect therapy) has not been achieved. Additionally, liposomal formulation of doxorubicin that release the drug following intravenous administration exhibited enhanced toxicity and increased doxorubicin accumulation in cardiac tissue.
What is needed in the art are new liposomal formulations of chemotherapeutic agents which do not suffer the drawbacks noted above. Surprisingly, the present invention provides such compositions.